A wide variety of relatively complex molecules, in particular drugs, can be produced by microorganisms during a fermentation process. Usually, the microorganism is fed with various assimilable sources of the elements required for the organism to produce the desired product.
The efficiency of production depends on a large number of factors, not least the nature of the carbon sources and the further conditions of fermentation. U.S. Pat. No. 4,231,938 (Merck) describes the cultivation of an Aspergillus microorganism in order to produce lovastatin.
U.S. Pat. No. 4,323,648 (Sankyo) also describes a process for the production of lovastatin this time using a microorganism of the genus Monascus.
Finally, U.S. Pat. No. 4,049,495 (also Sankyo) refers to the production of compactin using a Penicillium microorganism.
Buckland et al, Novel Microbial Products for Medicine and Agriculture, Eds. Demain et al, Chapter 19, 161-169 (1989, Society for Industrial Microbiology) describes the production of lovastatin by Aspergillus terreus. Fermentation development studies showed that for high lovastatin production, pH control and slow use of the carbon source was essential.
Although all of these documents refer to the production of various drugs by culturing different microorganisms, there are a number of problems associated with these processes. Most of them describe batch fermentation processes where the nutrients are added or mixed in with the microorganism in the culture medium at the beginning of the production process. Generally, (the fixed amount of) these nutrients are therefore gradually used up during fermentation. However, at the beginning of the process, because the nutrients are at relatively high concentrations, production of the drug is low because the microorganisms use carbon and nitrogen sources to grow, rather than to produce the drug. In such a process the rate of production of the drug is largely uncontrollable.
Overall production levels are low because in the batch processes nutrients are in effect supplied only once to the microorganism and so no variation (at least during production) can be conducted to balance growth of the biomass with production of the fermentation product.
The main objective of the invention is to provide a fermentation process that provides a greater degree of control and/or flexibility over production, so that the manufacturer can vary conditions to optimise production of the desired fermentation product. Surprisingly, it was found that feeding a nutrient not used to build up the compound of interest does increase the yield of the fermentation.